Tuning Energy Landscapes: Sequential Uphill and Downhill Pathways for Tetrasubstituted Carbon Construction

Abstract

The construction of vicinal tetrasubstituted carbon centers remains a synthetic challenge, mainly due to the reversible and endergonic nature of the C–C bond-forming process. Unlike exergonic transformations, strategies for overcoming the energetic penalty of uphill processes under thermal conditions have received comparatively little attention. Here, we report our experimental and computational studies on catalytic aerobic carbooxygenation, illuminating how the strategic balance between uphill and downhill energy profiles can be harnessed to construct vicinal tetrasubstituted carbon centers.

Keywords

Endergonic reactions - Tetrasubstituted carbon centers - Diastereoconvergency - Radicals - Molecular oxygen - Density functional calculation - Copper catalysis

Publication History

Received: 07 June 2025

Accepted after revision: 03 August 2025

Article published online:
19 August 2025

• References

• 1 Smith MB. March’s Advanced Organic Chemistry, Reactions, Mechanisms, and Structure. New Jersey: Wiley; 2020: 279
• 2a Borsley S, Gallagher JM, Leigh DA, Roberts BMW. Nat Chem Rev 2024; 8: 8
• 2b Borsley S, Leigh DA, Roberts BMW. Angew Chem Int Ed 2024; 63: e202400495
• 3a Wang H, Tian YM, König B. Nat Rev Chem 2022; 6: 745
• 3b Lin A, Lee S, Knowles RR. Acc Chem Res 2024; 57: 1827
• 4 Yudin AK. Chem Sci 2020; 11: 12423
• 5a Fischer H. Chem Rev 2001; 101: 3581
• 5b Leifert D, Studer A. Angew Chem Int Ed 2020; 59: 74
• 6a Sugawara M, Ohnishi R, Ezawa T. et al. ACS Catal 2020; 10: 12770
• 6b Sugawara M, Sawamura M, Akakabe M, Ramadoss B, Sohtome Y, Sodeoka M. Chem Asian J 2022; 17: e202200807
• 7a Sohtome Y, Sodeoka M. Pure Appl Chem 2024; 96: 5
• 7b Sohtome Y, Kanomata K, Sodeoka M. Bull Chem Soc Jpn 2021; 94: 1066
• 8 Because quaternary carbons are a subfamily of tetrasubstituted carbons, they are referred to herein as tetrasubstituted carbons for simplicity
• 9a Pierrot D, Marek I. Angew Chem Int Ed 2020; 59: 36
• 9b Romero KJ, Galliher MS, Pratt DA, Stephenson CRJ. Chem Soc Rev 2018; 47: 7851
• 9c Pitre SP, Weires NA, Overman LE. J Am Chem Soc 2019; 141: 2800
• 10a Pünner F, Sohtome Y, Lyu Y. et al. Angew Chem Int Ed 2024; 63: e202405876
• 10b Lyu Y, Pünner F, Akakabe M, Sohtome Y, Sodeoka M. Chem Asian J 2025; 20: e202500336

For selected reviews, see:
• 11a Huang H-M, Garduño-Castro MH, Morrill C, Procter DJ. Chem Soc Rev 2019; 48: 4626
• 11b Plesniak MP, Huang H-M, Procter DJ. Nat Rev Chem 2017; 1: 1
• 12 Logan AWJ, Parker JS, Hallside MS, Burton JW. Org Lett 2012; 14: 2940
• 13a Pelucchi M, Cavallotti C, Faravelli T, Klippenstein SJ. Phys Chem Chem Phys 2018; 20: 10607
• 13b Murakami Y, Oguchi T, Hashimoto K, Nakamura A, Sakai Y, Ando H. Int J Quantum Chem 1968; 2012: 112
• 14a Bhat V, Welin ER, Guo X, Stoltz BM. Chem Rev 2017; 117: 4528
• 14b Yus M, Nájera C, Foubelo F, Sansano JM. Chem Rev 2023; 123: 11817
• 15a Aufiero M, Gilmour R. Acc Chem Res 2018; 51: 1701
• 15b Patel A, Vella JR, Ma Z-X, Hsung RP, Houk KN. J Org Chem 2015; 80: 11888

For a recent review, see:
• 16 Shu C, Yang Z, Rajca A. Chem Rev 2023; 123: 11954
• 17 Ezawa T, Sohtome Y, Hashizume D. et al. J Am Chem Soc 2021; 143: 9094
• 18 Ito H, Kunii S, Sawamura M. Nat Chem 2010; 2: 972
• 19 Glendening ED, Landis CR, Weinhold F. Wiley Interdiscip Rev Comput Mol Sci 2012; 2: 1
• 20a Parsaee F, Senarathna MC, Kannangara PB, Alexander SN, Arche PDE, Welin ER. Nat Rev Chem 2021; 5: 486
• 20b De Vleeschouwer F, Van Speybroeck V, Waroquier M, Geerlings P, De Proft F. Org Lett 2007; 9: 2721
• 20c Héberger K, Lopata A. J Org Chem 1998; 63: 8646
• 21 Sohtome Y, Sodeoka M. Synlett 2020; 31: 523
• 22 Ren H, Dunet G, Mayer P, Knochel P. J Am Chem Soc 2007; 129: 5376
• 23 Liu W, Yu Z, Winssinger N. Org Lett 2021; 23: 969
• 24 Piotrowski JS, Li SC, Deshpande R. et al. Nat Chem Biol 2017; 13: 982
• 25 Drouin M, Hamel J-D, Paquin J-F. Synthesis 2018; 50: 881